Selective reduction of alkyne compounds

ABSTRACT

A process is provided for the preparation of cyclohexene derivatives of general formula I or II:  
                 
 
     in which the substituents R 1  and R 2  independently of one another are defined as follows:  
                 
 
     R 2  is OH or a protective group convertible to a hydroxyl group by hydrolysis,  
     R 3  and R 4  are hydrogen or C 1 —C 4 -alkyl, and  
     R 5  is hydrogen or C 1 —C 4 -acyl,  
     by the reduction or alkyne compounds of general formula III or IV:  
                 
 
     wherein the reducing agent used is at least one salt of hyposulfurous acid or hydroxymethanesulfinic acid or a mixture of at least one salt of hyposulfurous acid and at least one salt of hydroxymethanesulfinic acid.

[0001] The present invention relates to a novel process for thereduction of alkyne compounds. The invention relates in particular to aprocess for the preparation of cyclohexene derivatives suitable asintermediates for the preparation of carotinoids.

[0002] A large number of the industrial carotinoid syntheses describedin the literature, including the preparation of astaxanthine, proceedvia cyclohexene intermediates which contain a C≡C triple bond as well asone or more C═C double bonds. To form a conjugated double bond system,this triple bond has to be partially reduced in a separate process step.

[0003] In the context of the astaxanthine synthesis described in DE-A-4322 277, this partial reduction can take place with zinc/acetic acid inmethylene chloride in the case of the alkynediol IVa.

[0004] EP-A-0 005 748 relates to another process for the preparation ofastaxanthine, in which the partial reduction of the alkynediol offormula IIIa is also carried out with zinc/acetic acid in methylenechloride.

[0005] The disadvantage of the zinc/acetic acid reduction described isthe inadequate selectivity of the method. Unwanted by-products, e.g. theformation of spiro compounds which cannot be converted to the desiredsecondary products at a later stage of the synthesis, can causesignificant losses of yield. German patent application reference10049271.1 describes a process for the catalytic reduction of alkynecompounds using a mixture of zinc and at least one ammonium, copper,alkali metal or alkaline earth metal salt.

[0006] Other reduction processes are described inter alia in J. Amer.Oil Chem. Soc. 49 (1972) 72, in which triple bonds are reduced to cisdouble bonds in long-chain conjugated fatty acids with zinc in boilingprotic solvents.

[0007] The drastic reduction conditions mentioned here are unsuitablefor thermally labile compounds.

[0008] The reduction of conjugated alkynes in protic solvents isdescribed in Helv. Chim. Acta 58 (1975) 1016. The reducing agent used bythe authors is zinc dust activated by the addition of potassium cyanide.

[0009] On the one hand, the abovementioned methods give only moderateyields; on the other hand, activation with potassium cyanide carries aconsiderable health risk

[0010] The paper in Journal für praktische Chemie 336 (1994) 714-715contains a method for the (Z)-selective reduction of conjugated triplebonds with a combination of Zn and (Cu/Ag) in polar protic solvents,e.g. methanol/water.

[0011] This process has the disadvantage that the reagent is veryexpensive to prepare and moreover always has to be freshly prepared.

[0012] It was therefore an object of the present invention to provide aprocess for the partial reduction of alkyne compounds which avoided theabovementioned disadvantages of the state of the art.

[0013] We have found that this object is achieved by a process for thepreparation of cyclohexene derivatives of general formula I or II:

[0014] in which the substituents R¹ and R² independently of one anotherare defined as follows:

[0015] R² is OH or a protecting group convertible to a hydroxyl group byhydrolysis,

[0016] R³ and R⁴ are hydrogen or C₁—C₄-alkyl, and

[0017] R⁵ is hydrogen or C₁—C₄-acyl,

[0018] by the reduction of alkyne compounds of general formula III orIV:

[0019] in which the substituents R¹ and R² are as defined above, whereinthe reducing agent used is at least one salt of hyposulfurous acid orhydroxymethanesulfinic acid, or a mixture of at least one salt ofhyposulfurous acid and at least one salt of hydroxymethanesulfinic acid.

[0020] Alkyl radicals R³ and R⁴ which may be mentioned are linear orbranched C₁—C₄-alkyl chains, e.g. methyl, ethyl, n-propyl,1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and1,1-dimethylethyl. Preferred alkyl radicals are methyl and ethyl.

[0021] The radicals R³ and R⁴, together with the carbon atom to whichthey are bonded, can also form a cycloheptyl or cyclohexyl ring.

[0022] Substituents R⁵ which may be mentioned are linear or branchedC₁—C₄-acyl chains, e.g. formyl, acetyl, propionyl and isopropionyl. Thepreferred acyl radical is acetyl.

[0023] Suitable protective groups R² convertible to a hydroxyl group byhydrolysis are functional groups which can be converted to the hydroxylgroup relatively easily. Examples which may be mentioned are ethergroups such as

[0024] silyl ether groups such as —O—Si(CH₃)₃, —O—Si(CH₂CH₃)₃,—O—Si(isopropyl)₃, —O—Si(CH₃)₂(tert-butyl) and —O—Si(CH₃)₂(n-hexyl), orsubstituted methyl ether groups such as the α-alkoxyalkyl ether groupsof the formulae

[0025] and suitable pyranyl ether groups such as thetetrahydropyranyloxy group and the 4-methyl-5,6-dihydro-2H-pyranyloxygroup.

[0026] For R² it is particularly advantageous to use thetetrahydropyranyloxy group:

[0027] or the α-ethoxyethoxy group of the formula

[0028] Conditions for cleavage of the abovementioned protective groupscan be found inter alia in T. Greene “Protective Groups in OrganicChemistry”, John Wiley & Sons, 1981, Chapter 2.

[0029] Within the framework of the present invention, salts ofhyposulfurous acid are to be understood as meaning compounds of thegeneral formula M^(I) ₂(O₂S—SO₂), in which M^(I) is a monovalent metal,said salts preferably being sodium dithionite, potassium dithionite orzinc dithionite. Sodium dithionite may be mentioned as a particularlypreferred salt in this group.

[0030] Suitable salts of hydroxymethanesulfinic acid [HO—CH₂—S(═O)OH]are preferably sodium formaldehydesulfoxylate or zincformaldehydesulfoxylate, especially sodium formaldehydesulfoxylate.

[0031] In one preferred embodiment of the process according to theinvention, the reducing agent used is a mixture of at least one salt ofhyposulfurous acid and a base selected from the group comprising sodiumcarbonate, sodium hydrogencarbonate, potassium carbonate and potassiumhydrogencarbonate. A combination of sodium dithionite and NaHCO₃ hasproved to be a particularly advantageous reducing agent.

[0032] Blankit® (BASF Aktiengesellschaft), a reducing bleach based onsodium dithionite and sulfinic acid, is also suitable.

[0033] The following reducing agents can also be used:

[0034] calcium hydroxymethanesulfinate,

[0035] sulfoxylic acid compounds of other aldehydes such asacetaldehyde, benzaldehyde and butylaldehyde, and formamidinesulfinicacid.

[0036] The present invention further relates to a process for thepreparation of cyclohexene derivatives of formula I or II wherein sodiumdithionite is formed in situ, e.g. by the so-called formate process,where sodium formate is reacted with sodium hydrogensulfite in 80%methanol, the pH is then adjusted to approx. 9.5 by the addition of abase, and the agent to be reduced is then introduced into the reactionmixture.

[0037] Sodium dithionite can also be formed in situ via the so-calledborol process by reacting sodium hydridoborate with sodium hydroxidesolution and sulfur dioxide.

[0038] It has been found that the reduction according to the inventionproceeds particularly well in the presence of water. The amount of wateris chosen so that the base and the reducing agent are present indissolved form. As a rule, a total of 600 to 4000 ml of water,particularly preferably 800 to 1600 ml of water, are used per mole ofbase introduced and per mole of reducing agent.

[0039] The addition of an inert solvent has also proved advantageous forthe reduction process.

[0040] Suitable inert solvents in the process according to the inventionare generally any solvents inert towards the compounds I to IV. Thereaction is preferably carried out in chlorinated hydrocarbons, e.g.dichloromethane, perchloroethylene or chloroform, or in an etherealsolvent such as a dialkyl ether, tetrahydrofuran or dioxane, especiallyin the water-immiscible methyl tert-butyl ether. Other suitable solventsare aromatic hydrocarbons, especially toluene, and C₁—C₃-alcohols suchas methanol, ethanol or propanol.

[0041] It is preferred to use a 10 to 70% by weight solution of thealkynediol in one of the abovementioned solvents and particularlypreferred to use a 30 to 65% by weight solution of the alkynediol inmethylene chloride.

[0042] The reduction proceeds in a pH range of 6.0 to 10, preferably of7.8 to 9.

[0043] The sodium dithionite is used in an amount of about 1.1 to 5 gramatoms, preferably of 1.5 to 4 gram atoms and particularly preferably of2.1 to 3 gram atoms per mole of alkynediol to be reduced. To be able toobserve the pH range of 6.0 to 10 during the reduction process, 0.1 to 4mol of base, preferably 1 to 3.5 mol of base, are used per mole ofsodium dithionite.

[0044] The reduction can be carried out at temperatures between roomtemperature and the boiling point of the solvent used.

[0045] Preferred reaction temperatures range from 30 to 100° C.,particularly preferably from 40 to 80° C.

[0046] In one particularly preferred variant of the process according tothe invention, the reduction is carried out continuously, for example byreacting the reaction mixture, preferably consisting of alkynediols offormula IIIa or IVa, an organic solvent, water, a base and a reducingagent, in a tubular reactor or a series of stirred-tank reactors atelevated temperatures ranging from 30 to 100° C.

[0047] The process according to the invention is particularly suitablefor the preparation of the cyclohexene compounds of formulae Ia and IIa:

[0048] The general procedure for carrying out the process issuccessively to introduce water, base and alkyne compounds (in the caseof the cyclohexene compounds of formulae Ia and IIa, alkyne compounds offormula IIIa or IVa, dissolved in an inert solvent, are used):

[0049] and finally to introduce the reducing agent, either in portionsor all at once.

[0050] The subject of the present invention will be illustrated ingreater detail with the aid of the following Examples.

EXAMPLE 1

[0051] 12.5 g (0.05 mol) of6-hydroxy-3-(3-hydroxy-3-methyl-4-penten-1-ynyl)-2,4,4-trimethyl-2-cyclohexen-1-oneof formula IVa with a purity of 92%, dissolved in 15 ml of methylenechloride, are added to a solution of 14.6 g of NaHCO₃ in 225 ml of waterand the mixture was heated to 35° C., with stirring. 21.8 g (0.125 mol)of sodium dithionite were then introduced into the reaction mixture andstirring was continued for 50 minutes at 50° C. After cooling to 20° C.,100 ml of methylene chloride were added to the reaction mixture, theaqueous phase was separated off, the organic phase was washed with 2×100ml of water, dried over sodium sulfate and filtered and the residue waswashed with 2×100 ml of methylene chloride. Distillation of the solventgave an oily residue which, according to gas chromatographic analysis,contained 78.3 GC area % of alkenediol of formula IIa.

EXAMPLE 2

[0052] A mixture of 200 ml of water, 24.6 g (0.293 mol) of NaHCO₃, 25 g(0.1 mol) of alkynediol of formula IVa (purity: 92%) in 30 ml ofmethylene chloride, 100 ml of methanol and 38.36 g (0.22 mol) of sodiumdithionite was pumped through a tubular reactor preheated to 60 to 65°C. The discharge at the reactor outlet was run into a precooled receiverand the samples taken therefrom were analyzed by gas chromatography.According to GC, 30.5 area % of alkynediol of formula IVa and 66.7 area% of alkenediol of formula IIa were obtained.

We claim:
 1. A process for the preparation of cyclohexene derivatives ofgeneral formula I or II:

in which the substituents R¹ and R² independently of one another aredefined as follows:

R² is OH or a protecting group convertible to a hydroxyl group byhydrolysis, R³ and R⁴ are hydrogen or C₁—C₄-alkyl, and R⁵ is hydrogen orC₁—C₄-acyl, by the reduction of alkyne compounds of general formula IIIor IV:

in which the substituents R¹ and R² are as defined above, wherein thereducing agent used is at least one salt of hyposulfurous acid orhydroxymethanesulfinic acid or a mixture of at least one salt ofhyposulfurous acid and at least one salt of hydroxymethanesulfinic acid.2. A process as claimed in claim 1 wherein the reducing agent used issodium dithionite.
 3. A process as claimed in claim 2 wherein thereducing agent used is a mixture of sodium dithionite and a baseselected from the group comprising sodium carbonate, sodiumhydrogencarbonate, potassium carbonate and potassium hydrogencarbonate.4. A process as claimed in claim 1 wherein the reducing agent used issodium formaldehydesulfoxylate.
 5. A process as claimed in any of claims1 to 4 wherein the reduction is carried out in the presence of water. 6.A process as claimed in any of claims 1 to 5 wherein the reduction iscarried out in an organic solvent inert towards the cyclohexenederivatives of general formulae I to IV.
 7. A process as claimed in anyof claims 1 to 6 for the preparation of the cyclohexene compounds offormulae Ia and IIa.